Obesity is a condition of having a significantly greater body weight than an average body weight as a result of accumulation of neutral fat in fat cells due to continuous excess energy intake compared with energy consumption (Eiji Itagaki, “STEP series, Metabolism, Endocrinology”, Kaiba Shobo, 1st Ed., 1998, p. 105). It is known that the excessively-accumulated fat causes, for example, insulin resistance, diabetes, hypertension, hyperlipidemia, etc., and that a plurality of those factors as combined much increase a risk of onset of atherosclerosis; and the condition is referred to as a metabolic syndrome. Further, it is known that hypertriglyceridemia or obesity increases a risk of, for example, pancreatitis, hepatic dysfunction, cancer such as breast cancer, uterine cancer, ovarian cancer, colon cancer, prostate cancer, etc., menstrual abnormality, arthritis, gout, cholecystitis, gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), sleep apnea syndrome, etc. It is widely known that diabetes often leads to onset of, for example, angina pectoris, heat failure, stroke, claudication, retinopathy, reduced vision, renal failure, neuropathy, skin ulcer, infection, etc. [The Merck Manual of Medical Information, Domestic 2nd Ed., Merck & Co., 2003].
LCE is an enzyme existing in the endoplasmic reticula of cells, and is a type of an enzyme group that catalyzes the carbon chain elongation reaction of a fatty acid having at least 12 carbon atoms, specifically catalyzing the rate-determining condensation step of the reaction. In mammals, many fatty acids newly synthesized in the living bodies have a chain length of from 16 to 18 carbon atoms. These long-chain fatty acids constitute more than 90% of all the fatty acids existing in cells. These are important components of cell membranes, and are the essential ingredients of the fatty tissue that is the largest energy storage organ in animals. New fatty acid synthesis occurs most frequently in liver, and through the synthesis, the excessive glucose in a living body is converted into a fatty acid. Glucose is converted into a pyruvic acid salt through glycolysis, and the pyruvic acid salt is converted into a citric acid salt by mitochondria and then transferred to a cytosol. ATP citrate lyase in the cytosol produces an acetyl CoA that is a precursor of fatty acid and cholesterol. The acetyl CoA is carboxylated by an acetyl CoA carboxylate (ACC) to form a malonyl CoA. A multifunctional enzyme, fatty acid synthase (FAS) elongates a fatty acid by two carbons, using malonyl CoA, acetyl CoA and NADPH. In rodents, the main final product of FAS is palmitoyl CoA having 16 carbon atoms, and the carbon chain of the palmitoyl CoA is elongated by 2 carbons by LCE [Journal of Biological Chemistry, 276 (48), 45358-45366, (2001)]. It is known that excessive fatty acid synthesis promotion in living bodies increases neutral fat, etc., and finally causes fat accumulation. For example, WO2005/005665 (Patent Reference 1) shows a direct relationship between LCE and obesity. In addition, there is a report indicating the change in the expression level of mouse FACE (LCE) by eating (Matsuzaka T., et al., J. Lipid Res., 43(6): 911-920 (2002); Non-Patent Reference 1).
It is known that LCE exists also in protozoans and nematodes and participates in cell growth. For example, it is said that, in Trypanosoma protozoans that cause African trypanosomiasis (African sleeping sickness), a long-chain fatty acid is produced in a fatty acyl elongation route including LCE, and the intercellular fatty acyl elongation reaction inhibition may have some influence on the proliferation of Trypanosoma protozoans (Lee S. H., et al., Cell, 126: 691-699 (2006); Non-Patent Reference 2).
Any compound having an LCE inhibitory effect is heretofore not known at all. On the other hand, the compounds of the invention are derivatives having a sulfonyl on the saturated 6-membered ring thereof; however, compounds having an aryl or a heteroaryl bonding to the 3-position of a substituted sulfonyl saturated 6-membered ring via an amide bond or an urea bond therebetween are heretofore unknown.
Non-Patent Reference 1: J. Lipid Res., 43(6): 911-920 (2002)
Non-Patent Reference 2: Cell, 126: 691-699 (2006)